The overall objective of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals as a result of exposure to pesticides. The proposed research will focus on the anticholinesterase insecticides. It will examine the dynamic relationships among their sites of: 1) biotransformation, 2) primary action and 3) secondary action that are critical in determining their toxicity and that may be subject to modulation by other chemicals. It is expected that these toxicological studies will provide information useful in assessing the health hazards of pesticides, singly and in combinations, and will also further characterize the basic biological processes affected by these compounds. Specific hypotheses or questions to be addressed include: 1. Can activation and detoxication enzyme kinetics explain the mechanism by which piperonyl butoxide potentiates azinphos-ethyl toxicity six-fold in mice but reduced azinphos-methyl toxicity by three-fold? 2. Can the joint toxicities in mice and rats of combinations of related organophosphate insecticides be accurately predicted based on systematic in vitro kinetic analyses of events occurring at the sites of activation, sites of action and sites of detoxification for each of the compounds, singly and in combination. 3. Is the mechanism of the differential selective toxicities of azinphos-methyl (Guthion) and parathion in mammalian, avian and fish species due to species selective sensitivities of the brain acetylcholinesterases? 4. Is a reduced density (and/or affinity) of cholinergic receptors responsible for the tolerance that develops to the toxicity of organophosphate and carbamate insecticides? 5. Are there toxic interactions between OP insecticides and drugs via reactions at plasma albumin, lipid peroxidation or glutathione modulation? 6. Are OP insecticides metabolized significantly in the skin?